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Mettl3-mediated mRNA m⁶A modification controls postnatal liver development by modulating the transcription factor Hnf4a.

ABSTRACT: Hepatic specification and functional maturation are tightly controlled throughout development. N6-methyladenosine (m⁶A) is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. However, the function of m⁶A in liver development remains elusive. Here we dissect the role of Mettl3-mediated m⁶A modification in postnatal liver development and homeostasis. Knocking out Mettl3 perinatally with Alb-Cre (Mettl3 cKO) induces apoptosis and steatosis of hepatocytes, results in severe liver injury, and finally leads to postnatal lethality within 7 weeks. m⁶A-RIP sequencing and RNA-sequencing reveal that mRNAs of a series of crucial liver-enriched transcription factors are modified by m⁶A, including Hnf4a, a master regulator for hepatic parenchymal formation. Deleting Mettl3 reduces m⁶A modification on Hnf4a, decreases its transcript stability in an Igf2bp1-dependent manner, and down-regulates Hnf4a expression, while overexpressing Hnf4a with AAV8 alleviates the liver injury and prolongs the lifespan of Mettl3 cKO mice. However, knocking out Mettl3 in adults using Alb-Cre^ERT2 does not affect liver homeostasis. Our study identifies a dynamic role of Mettl3-mediated RNA m⁶A modification in liver development.

SUBMITTER: Xu Y

PROVIDER: S-EPMC9355946 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Mettl3-mediated mRNA m6A modification controls postnatal liver development by modulating the transcription factor Hnf4a.

Xu Yan Y Zhou Zhuowei Z Kang Xinmei X Pan Lijie L Liu Chang C Liang Xiaoqi X Chu Jiajie J Dong Shuai S Li Yanli Y Liu Qiuli Q Sun Yuetong Y Yu Shanshan S Zhang Qi Q

Nature communications 20220805 1

Hepatic specification and functional maturation are tightly controlled throughout development. N6-methyladenosine (m6A) is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. However, the function of m6A in liver development remains elusive. Here we dissect the role of Mettl3-mediated m6A modification in postnatal liver development and homeostasis. Knocking out Mettl3 perinatally with Alb-Cre ...[more]

PMID: 35931692

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Project description:BackgroundN6-Methyladenosine (m6A) methylation is the most prevalent internal posttranscriptional modification on mammalian mRNA. The role of m6A mRNA methylation in the heart is not known.MethodsTo determine the role of m6A methylation in the heart, we isolated primary cardiomyocytes and performed m6A immunoprecipitation followed by RNA sequencing. We then generated genetic tools to modulate m6A levels in cardiomyocytes by manipulating the levels of the m6A RNA methylase methyltransferase-like 3 (METTL3) both in culture and in vivo. We generated cardiac-restricted gain- and loss-of-function mouse models to allow assessment of the METTL3-m6A pathway in cardiac homeostasis and function.ResultsWe measured the level of m6A methylation on cardiomyocyte mRNA, and found a significant increase in response to hypertrophic stimulation, suggesting a potential role for m6A methylation in the development of cardiomyocyte hypertrophy. Analysis of m6A methylation showed significant enrichment in genes that regulate kinases and intracellular signaling pathways. Inhibition of METTL3 completely abrogated the ability of cardiomyocytes to undergo hypertrophy when stimulated to grow, whereas increased expression of the m6A RNA methylase METTL3 was sufficient to promote cardiomyocyte hypertrophy both in vitro and in vivo. Finally, cardiac-specific METTL3 knockout mice exhibit morphological and functional signs of heart failure with aging and stress, showing the necessity of RNA methylation for the maintenance of cardiac homeostasis.ConclusionsOur study identified METTL3-mediated methylation of mRNA on N6-adenosines as a dynamic modification that is enhanced in response to hypertrophic stimuli and is necessary for a normal hypertrophic response in cardiomyocytes. Enhanced m6A RNA methylation results in compensated cardiac hypertrophy, whereas diminished m6A drives eccentric cardiomyocyte remodeling and dysfunction, highlighting the critical importance of this novel stress-response mechanism in the heart for maintaining normal cardiac function.

Dataset Information

Mettl3-mediated mRNA m⁶A modification controls postnatal liver development by modulating the transcription factor Hnf4a.

Publications

Mettl3-mediated mRNA m<sup>6</sup>A modification controls postnatal liver development by modulating the transcription factor Hnf4a.

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